ENHANCING PERFORMANCE CAPACITY BY SPARING MUSCLE GLYCOGEN WITH MEDIUM CHAIN FATTY ACIDS

Abstract: A method of providing a preferential fuel to enhance performance by sparing muscle glycogen in a subject for undergoing high intensity physical activity by increasing medium chain fatty acid in the subject, particularly by administering a triglyceride of medium chain fatty acids to the subjet before or while the subject undergoes the physical activity.

Description: ENHANCING PERFORMANCE CAPACITY BY SPARING MUSCLE GLYCOGEN WITH MEDIUM CHAIN FATTY ACIDS FIELD OF THE INVENTION This invention relates to enhancing physical activity performance capacity. In particular, this invention relates to a method of sparing muscle glycogen in a subject by increasing medium chain fatty acids in the subject. More in particular, this invention relates to the use of a triglyceride of medium chain fatty acids to facilitate muscle glycogen sparing during periods of physical activity. BACKGROUND OF THE INVENTION Triglycerides are the principal form in which fats are eaten and stored in the body. Triglycerides are composed of two different compounds—fatty acids and glycerol. Three fatty acids are attached to each glycerol molecule as follows: H 2 COH H 2 C - OC(O)R HCOH + 3 fatty acids HC - OC(O)R- + 3 H 2 O 1 H 2 COH H 2 C - OC(O)R" glycerol triglyceride where R, R' and R" are the same or different fatty acid side chains. The fatty acid side chain comprises a chain of carbon atoms onto which are bonded hydrogen and oxygen atoms. These chains vary in degree of saturation with hydrogen and length. Fatty acids are classified as saturated, monounsaturated or polyunsaturated depending upon the number of hydrogen atoms. For the purposes of this document, short chain fatty acids are defined as containing fewer than six carbons, medium chain fatty acids contain six to twelve carbons, and long chain fatty acids contain fourteen or more carbons. Most fats are present in food as triglycerides of long chain fatty acids (LCFAs) . After ingestion, these triglycerides are broken down into LCFAs, monoglycerides, and glycerol which are absorbed into the cell walls of the small intestine. In order to be transported into the body, the LCFAs are then packaged in a fat droplet called a chylomicron. Chylomicrons pass into the lymphatic system and then slowly into the blood stream from which they are subsequently removed by the liver. The chylomicron is then broken down into smaller components called lipoproteins, which are circulated throughout the bloodstream to various tissues, particularly adipose fat storage tissue. LCFAs can be released through further complex processes from the adipose tissue to provide a source of energy to the muscle under certain exercise conditions. During exercise, triglycerides of medium chain fatty acids (MCFAs) may provide a more readily available source of energy to the muscle because they are metabolized differently than LCFAs. 1. After triglycerides of MCFAs are ingested, MCFAs are released from the triglyceride backbone at higher rates than LCFAs by digestive enzymes in the small intestine. 2. MCFAs, being more soluble in the blood than LCFAs, are transported and circulated differently throughout the body. MCFAs are absorbed directly through the wall of the small intestine. MCFAs are then released directly into the blood stream that flows to the liver. This is unlike LCFAs which must be packaged into chylomicrons for transport in the body. 3. Any fatty acid must enter the mitochondria to be utilized as an energy source. In the case of LCFAs, a substance called carnitine is required for transport into the mitochondria. Unlike LCFAs, MCFAs can enter the mitochondria without the help of carnitine due to their shorter chain length. MCFAs are converted within the liver to form ketone bodies. These ketone bodies, uniquely derived from MCFAs, may be transported to the muscle to be used as an additional energy source. Owing to their increased solubility, some MCFAs may bypass the liver and be directly transported to mitochondria located within the muscle as a further source of energy. So, due to these three main differences in metabolism of fatty acids with different chain lengths, MCFAs may provide the muscle with readily available energy. Physical activity, among other factors, is dependent upon the body's ability to store, deliver and restore energy sources. The diet provides energy mainly from carbohydrates and fats. These energy sources are stored in the body until needed. Protein is not used as an energy source unless the body is in a calorie restricted state. Proteins are the body's building blocks needed for growth and repair of damaged cells such as muscle tissue. Muscles use energy at a rate proportional to the intensity of physical activity. Energy is produced when the mitochondria contained within muscle cells burn up carbohydrate and fatty acids in the presence of oxygen to make a biochemical compound called ATP. ATP is the substance that actually provides the direct source of energy to the muscles. ATP can also be produced by alternative mechanisms without oxygen, but in this case only carbohydrates and not fats are used. Although fat provided in the diet can be an important energy source during exercise, most emphasis is placed on the intake and use of carbohydrates. This has resulted from research showing that the use of LCFAs by the muscle during exercise typically decreases as exercise intensity increases. For example, during walking or low intensity exercise, the body uses LCFAs more efficiently than during a fast jog or sprint or high intensity exercise. This inefficiency at higher intensities is primarily due to the inability of the blood to provide LCFAs to the muscle. As exercise intensity increases, the blood vessels narrow or constrict in the adipose tissue in order to provide adequate blood flow to the working muscles. Blood vessel constriction in the adipose at these high exercise intensities decreases blood flow to the muscle limiting the availability of albumin, a necessary compound required to transport LCFAs in the blood. Therefore, LCFA availability is a limiting factor for the muscle to use fat as an energy source during high intensity exercise. Exercise intensity is defined as the tempo, speed or resistance of an exercise. Intensity can be increased by working faster—doing more work in a given period of time. It is generally measured by evaluating the metabolic response of an individual challenged by exercise of increasing intensity, therefore increasing oxygen consumption (V0 2 ) . A point is reached where, even though the exercise intensity can be increased still further, there is no accompanying increase in oxygen uptake. This is called the maximum oxygen uptake (V0 2 max) , and is related to size, age, sex, genetic potential and level of habitual activity of the individual. The relative intensity of the oxygen cost of an activity is expressed as a percentage of V0 2 max. The relative exercise intensity reflects the physiological and psychological demands on an individual more than the absolute values for work loads. Despite this theoretical basis, research groups in the exercise science field did not show any advantage in performance of using triglycerides of MCFAs versus carbohydrate or triglycerides of LCFAs. In this respect, J. L. Ivy et al., Int. J. Sports Medicine (1980) 1: 15-20 describes that ten well- trained men participated in 60 minutes of exercise on a bicycle ergometer or a motor driven treadmill at 70% of the subjects' V0 2 max (as described earlier) . Subjects randomly consumed a control containing only carbohydrate (CHO) , 30 grams of triglyceride of MCFAs, otherwise known as medium chain triglyceride (MCT) , mixed into cereal with skim milk, and 30 grams of triglyceride of LCFAs, otherwise known as long chain triglycerides (LCTs) , mixed into cereal with skim milk. All meals were consumed 1 hour before the exercise. Based on the respiratory exchange ratio, the percentage of total energy used by the subject obtained from fat metabolism during all trials was similar. It was concluded that "MCT in combination with carbohydrate is not a viable energy source during an acute endurance exercise." J. Deco baz et al., Eur. J. Appl. Physiol. (1983) 52: 9-14 followed up the Ivy et al. 1980 study and describes that twelve subjects exercising at 60% of their V0 2 max on a bicycle ergometer for 1 hour found no advantage of ingesting test meals of only MCTs versus carbohydrate (maltodextrin, D.E. = 22). Both test meals provided approximately 238 calories and were presented as a hot, instant decaffeinated coffee drink (300 ml) to aid in the palatability of the test materials. The MCT had previously been prepared as a powdered emulsion with caseinate. The effects of MCT and carbohydrate on energy metabolism and glycogen levels were compared by measuring C0 2 output (break down products of carbohydrate and fat after their use for energy) , glycogen concentrations via muscle biopsies, and ketone levels (fat by-products) in the blood. The glycogen concentration in the working muscles decreased equally, about 55%, in both groups. They concluded that, with normal carbohydrate stores, the ingestion of MCT did not decrease the contribution of carbohydrate during the exercise protocol. E. Auclair et al., Eur. J. Appl. Physiol. (1988) 57: 126-131 describes a method to test the premise that fat ingestion could increase endurance by slowing the rate of glycogen depletion. Trained rats ran on a rodent treadmill following infusion of water, glucose, MCTs or LCTs. The intake of MCTs or LCTs did not reduce glycogen use in liver, heart or skeletal muscle. The conclusion was made that increased fat availability before exercise did not modify glycogen depletion. Finally, D. Massicotte et al., J. Applied Physiology, October (1992) 1334-39 describes subjects participating in 2 hour exercise rides on a bicycle ergometer at 65% of their maximum oxygen uptake (V0 2 max) . Test diets of MCT compared with carbohydrate were ingested 1 hour prior to the exercise ride. 25 grams of MCT in a hot drink flavored with vanilla were ingested 1 hour before the beginning of exercise and compared with the ingestion of a 6% glucose solution. Ingestion of MCT or glucose did not contribute to the reduction of endogenous carbohydrate utilization. This study by Massicotte et al. is unique in contrast to the previously described studies in that glucose and MCTs were labeled with a 13 C tracer to assess more accurately their use for energy throughout the exercise bout. Subjects break down the labeled MCT and glucose as 13 C0 2 which is easily measured in the expired breath. The contribution of MCT and carbohydrate to the total energy expenditure as measured with a 13 C tracer was not statistically significantly different. These exercise studies have not found MCTs as a unique energy source under the conditions tested. As previously stated, MCFAs are metabolized differently than LCFAs. MCFAs may provide a readily available source of energy to the muscle when blood flow is constricted during a high intensity exercise. The discovery that this preferential use of MCFAs by the muscle would decrease the muscle's reliance on its major carbohydrate store, glycogen, would be a substantial advance in the technology of enhancing physical activity performance capacity. The amount of glycogen is limited and the depletion of this fuel is a limitation on duration and intensity of exercise. OBJECTS OF THE INVENTION It is thus an object of the invention to provide a means for enhancing physical activity performance capacity. It is another object of this invention to provide a method of sparing muscle glycogen in a subject during periods of high intensity physical activity. These and other objects of the invention will be readily apparent from the following description and claims. SUMMARY OF THE INVENTION It has been found for the first time that MCFAs can be made available to the muscle and utilized as an additional fuel source to muscle glycogen and blood glucose at high exercise intensities. It has also been found for the first time that providing medium chain fatty acids to the body reduces the rate of muscle glycogen utilization under certain exercise conditions. The maintaining of muscle glycogen levels tends to: (1) increase the exercise time before muscle exhaustion is manifested, (2) decrease the time required for glycogen to be restored to capacity prior to the next physical activity, and (3) increase interval training capacity—train more in a given period of time. It has further been found that consumption of a product containing triglycerides of MCFAs provided a benefit in the sprint phase at the end of an endurance activity. Specifically, in sprints at greater than 70% of V0 2 max at the end of an extended exercise bout at 50% of V0 2 max, performance capacity was enhanced, even though a product containing triglycerides of MCFAs was consumed prior to the low intensity exercise indicating that the MCFAs were held in reserve for the sprint. Under certain test conditions, there was a greater glycogen sparing effect (or lowering of the glycogen utilization rates) for subjects who consumed a product containing a mixture of triglycerides of MCFAs and carbohydrate compared to other products containing triglycerides of LCFAs and carbohydrate or carbohydrate alone. The glycogen utilization rate (amount of muscle carbohydrate used per minute during exercise) for each subject consuming a product containing triglycerides of MCFAs and carbohydrate was significantly reduced in comparison to subjects who consumed products containing either carbohydrate alone or carbohydrate and triglycerides of LCFAs at the same caloric intake. This indicates that subjects who consume triglycerides of MCFAs can use less muscle carbohydrate during physical activity levels which primarily rely on muscle glycogen as a carbohydrate source. Nevertheless, how effective these potential benefits are depends upon the duration and intensity of the exercise bout. In one aspect, the present invention is a method of providing a preferential fuel to enhance performance, particularly a method of sparing muscle glycogen in a subject by increasing medium chain fatty acid for undergoing physical activity at an intensity of greater than 70% of V0 2 max. Advantageously, the concentration of medium chain fatty acid is increased by administering a triglyceride of a least one medium chain fatty acid, particularly by administering a triglyceride of three medium chain fatty acids, to the subject. The medium chain fatty acids are saturated or unsaturated fatty acids having 6 to 12 carbon atoms. Advantageously, the medium chain fatty acids are saturated fatty acids having 6 to 12 carbon atoms, particularly a saturated fatty acid having 10 carbon atoms. The triglyceride is administered in an amount effective for sparing muscle glycogen, preferably 1 to 500 grams, more preferably 4 to 50 grams. Advantageously, the physical exercise intensity is at greater than 70% of V0 2 max, more preferably at least 75% of V0 2 max, still more preferably at least 85% of V0 2 max. The medium chain triglyceride may be administered in a solid or liquid form. Preferably, the triglyceride is administered by ingestion. The triglyceride may be administered together with a carbohydrate and/or other ingredients. The concentration of medium chain fatty acid is increased before the subject undergoes the physical activity or while the subject undergoes the physical activity. The invention is also a method of sparing muscle glycogen in a subject by increasing medium chain fatty acid in the subject for undergoing physical activity at a level of muscle activity at which glycogen would be metabolized as a source of energy, particularly a method of enhancing physical activity performance capacity of a subject by administering to the subject a triglyceride of medium chain fatty acids for undergoing physical activity at an intensity greater than 70% of V0 2 max. DETAILED DESCRIPTION OF THE INVENTION The present invention is further described and illustrated in the following examples. Further objects of this invention, together with additional features contributing thereto and advantages accruing therefrom, will be apparent from the following examples of the invention. It will be appreciated that variations and modifications to the products and methods can be made by the skilled person without departing from the spirit or scope of the invention as defined in the appended claims. EXAMPLE 1 After consumption of a solid food bar (the MCT product) containing 16% by weight of triglycerides of capric acid (tricaprin) and 73% by weight carbohydrate, or an otherwise identical solid food bar (the LCT product) wherein the 16% by weight tricaprin is replaced by 16% by weight of partially hydrogenated soybean oil, glycogen use rates were compared during similar exercise protocols at 85% of V0 2 max for 30 minutes. EXERCISE PROTOCOL Ten (n=10) highly trained, male competitive cyclists, classified as national caliber cyclists, participated in this study. All subjects performed all exercise bouts in a double-blind random order. The cyclists completed three 30 minute rides on separate days during which the two different dietary treatments were randomly assigned. Workloads, based on economy tests prior to participation in the study, corresponded to intensities of 85% of maximum oxygen uptake (85% V0 2 max) . The exercise bout was of a continuous nature with no rest intervals during the 30 minute exercise regimen. Subjects were tested in the morning in the fasted state. One hour prior to the start of the 30 minute exercise bout, subjects consumed 100 grams of the MCT product or 100 grams of the LCT product. BLOOD ANALYSIS Blood analysis was done before, at 15 minutes and after the 30 minute ride. Blood samples were analyzed for (1) glucose, (2) insulin, (3) free fatty acids, (4) triglycerides, (5) glycerol, and (6) ketone bodies. MUSCLE ANALYSIS A muscle biopsy of the vastuε lateralis was taken prior to the exercise bout and after the 30 minute ride. Muscle samples were analyzed for glycogen. MUSCLE GLYCOGEN USE The amount of muscle carbohydrate used per minute during exercise was significantly less for subjects consuming the MCT product versus the LCT product under identical exercise protocols. The results were as follows: Glycogen Utilization Rate (mmol/kg/min) MCT product 0.46 LCT product 1.01 BLOOD PARAMETERS There was no significant difference between blood values of fatty acids, ketones, glucose or insulin at the end of the exercise bouts for all treatment groups. This indicates that fatty acids and ketones provided by the MCT product were used immediately as a source of energy. Glycerol, the backbone of the triglycerides of capric acid and of LCFAs, was present at higher levels for the subjects consuming the MCT product versus the LCT product. This indicates that MCFAs were being removed from the glycerol backbone more readily than LCFAs during the exercise protocol. EXAMPLE 2 After consumption of 100 grams of the MCT product of Example 1 or the caloric equivalent of carbohydrate only, glycogen use rates were compared during similar exercise protocols at 85% of V0 2 max for 30 minutes. The test protocol was the same as in Example 1. MUSCLE GLYCOGEN USE The amount of muscle carbohydrate used per minute during exercise was significantly less for subjects consuming the MCT product versus the subjects given carbohydrate alone under identical exercise protocols. The results were as follows: Glycogen Utilization Rate (mmol/kg/min) MCT product 0.46 Carbohydrate 1.09 BLOOD PARAMETERS There was no significant difference between blood values of fatty acids, ketones, glucose or insulin at the end of the exercise bouts for all treatment groups. This indicates that fatty acids and ketones provided by the MCT product were used immediately as a source of energy. Glycerol, the backbone of the triglycerides of capric acid, was present at high levels for subjects consuming the MCT product indicating that MCFAs were being removed from the triglyceride backbone during the exercise protocol. EXAMPLE 3 After consumption of 100 grams of the MCT product of Example 1 or the caloric equivalent of carbohydrate only, glycogen use rates were compared during similar exercise protocols at 100% of V0 2 max for 5 minutes. The test protocol was similar to Example 1, however five subjects were tested. MUSCLE GLYCOGEN USE The amount of muscle carbohydrate used per minute during exercise was significantly less for subjects consuming the MCT product versus the subjects given carbohydrate alone under identical exercise protocols. The results were as follows: Glycogen Utilization Rate (mmol/kg/min) MCT product 0.66 5.44 Carbohydrate BLOOD PARAMETERS Again, there was no significant difference between blood values of fatty acids, ketones, glucose or insulin at the end of the exercise bouts for all treatment groups. This indicates that fatty acids and ketones provided by the MCT product were used immediately as a source of energy. Glycerol, the backbone of the triglycerides of capric acid, was present at high levels for subjects consuming the MCT product indicating that MCFAs were being removed from the triglyceride backbone during the exercise protocol. EXAMPLE 4 After consumption of 100 grams of the MCT product of Example 1 or the caloric equivalent of carbohydrate only, glycogen use rates were compared during similar exercise protocols at 65% of V0 2 max for 60 minutes. The test protocol was similar to Example 1, however four subjects were tested at 65% of V0 2 max for 60 minutes. MUSCLE GLYCOGEN USE The amount of muscle carbohydrate used per minute during exercise was slightly higher for subjects consuming the MCT product versus the subjects given carbohydrate alone under identical exercise protocols. The results were as follows; Glycogen Utilization Rate (mmol/kg/min) MCT product 0.70 Carbohydrate 0.28 BLOOD PARAMETERS Blood values of glucose and insulin at the end of the exercise bouts were slightly higher for all subjects consuming carbohydrate versus the MCT product as expected. Blood values of triglycerides, free fatty acids, glycerol, and ketones were not significantly different for either treatment group. This indicates that fatty acids were also provided by endogenous sources of triglycerides during this low intensity exercise. EXAMPLE 5 After consumption of 100 grams of the MCT product of Example 1 or the caloric equivalent of carbohydrate only, glycogen use rates were compared during similar exercise protocols at 50% of V0 2 max for 60 minutes. The test protocol was similar to Example 1, however four subjects were tested at 50% of V0 2 max for 60 minutes. MUSCLE GLYCOGEN USE The amount of muscle carbohydrate used per minute during exercise was not significantly different for subjects consuming the MCT product versus the subjects given carbohydrate alone under identical exercise protocols. The results were as follows: Glycogen Utilization Rate (mmol/kg/min) MCT product 0.45 Carbohydrate 0.40 BLOOD PARAMETERS Blood values of glucose and insulin at the end of the exercise bouts were slightly higher for all subjects consuming carbohydrate versus the MCT product as expected. Blood values of triglycerides, free fatty acids, glycerol, and ketones were not significantly different for either treatment group. This indicates that fatty acids were also provided by endogenous sources of triglycerides during this low intensity exercise. EXAMPLE 6 Immediately after the exercise protocol described in Example 5, performance testing was measured as follows. After the post biopsy, subjects performed one-minute intervals at 115% of V0 2 max with a 1:1 work:rest ratio. Subjects continued until they could not maintain a cadence of greater than 60 RPM or until they completed 10 intervals, whichever came first. The time of the performance test is the total number of seconds of work, not counting rest intervals. PERFORMANCE TESTING RESULTS TEST TIME (seconds) MCT product 308 Carbohydrate 145 All subjects that participated in the performance testing after riding for 60 minutes at 50% of V0 2 max performed longer due to the ingestion of the MCT product prior to exercise. Although the study was double-blind in nature, it was noted in the results that all subjects commented after completion of the study that the ride performed after only carbohydrate ingestion was significantly more difficult than the ride after the ingestion of the MCT product. It was also noted that riders worked visibly harder during the carbohydrate performance test. Although the rate of glycogen utilization was not different during the 60 minute ride at 50% of V0 2 max, after exercise intensity was increased to 115% of V0 2 max, there was a positive impact on performance time. The maintaining of muscle glycogen levels increased the exercise time before muscle exhaustion was manifested. This will decrease the time required for glycogen to be restored to capacity prior to the next physical activity, and increase the capacity to train more in a given period of time. EXAMPLE 7 Immediately after the exercise protocol described in Example 4, performance testing was measured on only two of the four subjects as follows. After the post biopsy, subjects performed one-minute intervals at 115% of V0 2 max with a 1:1 work:rest ratio. Subjects continued until they could not maintain a cadence of greater than 60 RPM or until they completed 10 intervals, whichever came first. The time of the performance test is the total number of seconds of work, not counting rest intervals. PERFORMANCE TESTING RESULTS TEST TIME (seconds) MCT product Subject 1 227 Subject 2 600 Carbohydrate Subject 1 176 Subject 2 600 All subjects that participated in the performance testing after riding for 60 minutes at 65% of V0 2 max performed longer due to the ingestion of the MCT product prior to exercise. Again it was noted that both subjects commented after the completion of the study that the ride performed after only carbohydrate ingestion was significantly more difficult than the ride after the ingestion of the MCT product. One subject rode for 10 intervals, the maximum, for both products. It was also noted that riders worked visibly harder during the carbohydrate performance test. Although the rate of glycogen utilization was not different during the 60 minute ride at 65% of V0 2 max, after exercise intensity was increased to 115% of V0 2 max, there was a positive impact on performance time. The maintaining of muscle glycogen levels increased the exercise time before muscle exhaustion was manifested. This will decrease the time required for glycogen to be restored to capacity prior to the next physical activity, and increase the capacity to train more in a given period of time.

Claims: WHAT IS CLAIMED IS: 1. A method of sparing muscle glycogen in a subject, which comprises increasing medium chain fatty acid in the subject for undergoing physical activity at an intensity greater than 70% of V0 2 max. 2. A method as claimed in claim 1, wherein the medium chain fatty acid is increased by administering a triglyceride of at least one medium chain fatty acid to the subject. 3. A method as claimed in claim 1, wherein the medium chain fatty acid is increased by administering a triglyceride of three medium chain fatty acids to the subject. 4. A method as claimed in claim 3, wherein the medium chain fatty acids are saturated or unsaturated fatty acids having 6 to 12 carbon atoms. 5. A method as claimed in claim 4, wherein the medium chain fatty acids are saturated fatty acids having 6 to 12 carbon atoms. 6. A method as claimed in claim 5, wherein the medium chain fatty acids are saturated fatty acids having 10 carbon atoms. 7. A method as claimed in claim 2, wherein the triglyceride is administered by ingestion. 8. A method as claimed in claim 2, wherein the triglyceride is administered together with a carbohydrate. 9. A method as claimed in claim 1, wherein medium chain fatty acid is increased before the subject undergoes the physical activity. 10. A method as claimed in claim 1, wherein medium chain fatty acid is increased while the subject undergoes the physical activity. 11. A method as claimed in claim 2, wherein the triglyceride is administered in an amount effective for sparing muscle glycogen. 12. A method as claimed in claim 3 , wherein the triglyceride is administered in an amount effective for sparing muscle glycogen. 13. A method as claimed in claim 12, wherein the amount is 1 to 500 grams. 14. A method as claimed in claim 13, wherein the amount is 10 to 25 grams. 15. A method as claimed in claim 1, wherein the subject is a human. 16. A method as claimed in claim 1, wherein the physical exercise intensity is at least 75% of V0 2 max. 17. A method as claimed in claim 1, wherein the physical exercise intensity is at least 85% of V0 2 max. 18. A method as claimed in claim 3, wherein the triglyceride is administered in solid form. 19. A method as claimed in claim 3, wherein the triglyceride is administered in liquid form. 20. A method of enhancing physical performance capacity of a subject, which comprises administering to the subject a triglyceride of medium chain fatty acids for undergoing physical activity at an intensity greater than 70% of V0 2 max.

Inventors: BEYER DANIEL L, BRADLEY DONDEENA G, DEHNEL ROGER B, DREHER MARK L, JEROME RALPH A, BEYER, DANIEL, L., BRADLEY, DONDEENA, G., DEHNEL, ROGER, B., DREHER, MARK, L., JEROME, RALPH, A.
Applicants: MARS INC, MARS, INCORPORATED
Application year: 1994
Main classification: A61K31
IPC codes: A61K31